Molecular genetics of all known COL4A1-A2 disease
Dr. Elisabeth Tournier Lasserve, from the Service of Molecular Neurovascular Genetics, Saint-Louis Hospital, Paris and University of Paris, INSERM, Paris, France, in her presentation titled “Molecular genetics of all known COL4A1/COL4A2 diseases,” thanked the Association for the important moment of discussion. She focused on the genetic mutations associated with known COL4A1/COL4A2 diseases.
Dr. Tournier Lasserve explained that various types of mutations affect the COL4A1 and COL4A2 genes, each leading to different effects on the corresponding proteins.
Missense mutations are one of the main types discussed. These mutations involve the substitution of one amino acid for another in the protein sequence. When it concerns glycine residues in the Gly-X-Y motif present in the triple helix portion of the protein, the resulting mutated protein cannot be properly secreted into the cell matrix, causing toxic effects on the cell.
Another type of mutation discussed is the premature stop codon. A stop codon is an information unit in the genetic code, consisting of a sequence of three nucleotides in DNA and the corresponding messenger RNA, which serves as a signal to stop reading and indicates that protein production is complete. In this case, the DNA sequence contains an erroneous stop signal, leading to the production of an incomplete and therefore non-functional protein. Insufficient production of the protein can have serious repercussions on the patient’s health.
Dr. Tournier Lasserve also mentioned the PADMAL mutation and the duplications or triplications of the COL4A1/COL4A2 genes. In both cases, these mutations lead to an increased regulation of these genes, causing a pathological mechanism very different from stop codon mutations. In fact, there is what is called the upregulation of COL4A1/A2, which results in an increase in the amount of protein produced, potentially causing a functional and pathological overload of the cells.
During her presentation, Dr. Tournier Lasserve illustrated these concepts with various clinical examples, showing how different mutations can manifest differently in patients. Each example highlighted the specific consequences of the mutations on the COL4A1 and COL4A2 proteins, emphasizing the importance of accurate diagnosis and a detailed understanding of the mutations for effective treatment of related diseases.
In France, all patients with cerebral small vessel disease (CSVD) report to their medical center, and between 2016 and 2020, they received more than 3000 patients, 80% of whom were adults and 20% children or fetuses. Genetic analysis of these patients revealed that 1.6% had mutations in the COL4A1 or COL4A2 genes, particularly glycine missense mutations or stop codon mutations. These mutations are associated with a range of symptoms with highly variable phenotypes. In addition to neurological manifestations such as brain haemorrhages, vascular leukoencephalopathies, and retinal artery tortuosity, there can also be a series of extra-neurological manifestations, including:
- Ocular anomalies,
- Neural anomalies,
- Renal cysts,
- Hematuria,
- Intra and extracranial aneurysms.
These manifestations can vary significantly between adults and children.
Another condition related to the COL4A1 and COL4A2 genes, although primarily with COL4A1, is PADMAL (Pontine Autosomal Dominant MicroAngiopathy & Leukoencephalopathy). This condition was first described by a German group in 2004, after studying since 1993 a particular family from Hamburg affected by CSVD that transmitted the disease in an autosomal dominant genetic manner. This family had a high incidence of pontine infarcts and dementia.
Through exome sequencing analysis, it was demonstrated that the six PADMAL pathologies were associated with mutations located in a non-coding region related to microRNA miR-29. These mutations cause increased expression of the COL4A1 gene, both at the messenger RNA and protein levels.
The phenotype of this disease is very characteristic and distinct from CSVD, presenting with recurrent pontine infarcts, hemispheric lacunar infarcts, and vascular leukoencephalopathies. It is important to note that no fetuses or children were affected, while young adults (between 35 and 45 years old) were affected. There were no brain haemorrhages or extra-neurological symptoms. The researchers therefore checked, with negative results, if miR-29 was also involved in CSVD.
Dr. Tournier Lasserve then focused on analyzing other mutations that cause increased expression of COL4A1/A2 to determine if they were involved in CSVD. She illustrated how duplications or triplications of the number of copies of COL4A1/A2 can lead to CSVD. Analyzing six families with these characteristics, the researchers noticed the presence of pontine infarcts, which, although not specific, were frequent, and unlike PADMAL, the presence of aneurysms and dolicho-basilar arteries. However, it is still unclear why, unlike PADMAL, arteries are involved in these cases.
She concluded her presentation by asserting that different classes of mutations in COL4A1 lead to different phenotypes of CSVD, which in turn raise various questions that will be answered in the future.
